A remarkable variety of fundamental physiological functions in most organisms is controlled by the circadian clock. This is a time-tracking system intrinsic to most organisms that enables the adaptation to environmental changes. Disruption of circadian rhythms has profound influence to human health and has been linked to depression, insomnia, jet lag, coronary heart disease and a variety of neurodegenerative diseases. Thereby, the molecular mechanisms governing the circadian clock constitute a very attractive hold for the understanding of the links to physiology and metabolism, representing potential tools for the development of therapeutic strategies. Remarkably, 10-15% of all mammalian transcripts undergo circadian fluctuations in their expression levels. Thus, genome-wide mechanisms must operate in order to insure such global transcriptional regulation. Our recent studies (Cell 2006 125: 497-508) have established that CLOCK, a master controller of circadian rhythms, directly modifies chromatin. CLOCK possesses intrinsic enzymatic histone acetyltransferase (HAT) activity, demonstrating that control of chromatin remodeling constitutes a key regulatory step governing the circadian clock machinery. This finding has multiple molecular and physiological implications and paves the way to a number of important in vitro and in vivo studies that are central to this proposal. We will use a range of molecular, genetic and biochemical approaches to gain insights into chromatin remodeling mechanisms that are likely to govern the physiological mechanism of the circadian clock. Another goal is to unravel how clock-mediated signaling may 'talk'to the enzymatic function of CLOCK, and thereby establish a direct link between physiology and chromatin remodeling. A final goal is to decipher the extent of CLOCK-mediated acetylation, by identifying the natural substrates of its enzymatic activity. We predict that these studies will provide novel and important insights into how circadian physiology and metabolism are controlled by chromatin remodeling. The circadian clock governs a large variety of our rhythmic physiology, including sleep-wake cycles, metabolism and hormonal levels. This proposal is aimed at deciphering the intimate mechanisms by which the circadian clock operates. Specifically, we will unravel the function that chromatin, the proteinaceous scaffold of DNA, has in these processes.